Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.

A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1ß, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

Early Detection of Subclinical Atherosclerosis: Hyperhomocysteinemia as a Promising Marker in Adolescents With Vitamin B Deficiency.

In recent decades, the increased incidence of cardiovascular disease (CVD) mortality among young adults has raised concerns. Although clinical manifestations of CVD typically occur later in life, the underlying pathological processes emerge early on. This review article summarizes the association between vitamin B deficiency-induced hyperhomocysteinemia and subclinical atherosclerosis in adolescents. Numerous studies have demonstrated that elevated homocysteine levels are an independent risk factor for endothelial dysfunction (ED) and arterial stiffness, which are key contributors to CVD. Notably, vitamin B deficiency, particularly in vitamin B9 and vitamin B12, emerges as a significant factor in childhood hyperhomocysteinemia, initiating the development of subclinical atherosclerosis in early life. A comprehensive review of relevant literature from prominent bibliographic databases, including PubMed/MEDLINE, PubMed Central, Google Scholar, and Cochrane, was performed. Four cross-sectional studies focusing on homocysteine levels as an exposure variable and markers of atherosclerosis as outcome measures were included and reviewed as part of our analysis. The reviewed studies demonstrate a positive correlation between homocysteine levels and markers of atherosclerosis, including increased carotid intima-media thickness (CIMT) and ED. Mainly, adolescents with vitamin B12 deficiency exhibit a significant positive correlation between homocysteine levels and CIMT. These findings underscore the potential of hyperhomocysteinemia as an early marker for detecting subclinical atherosclerosis in adolescents with vitamin B deficiency. Despite limited research in this area, recognizing the importance of early detection and management of subclinical atherosclerosis in adolescents can help mitigate the risk of severe cardiovascular events such as myocardial infarction and stroke in young adulthood.

The prevalence of gender stereotypes in pharmacy student simulated counseling sessions utilizing standardized patients.

INTRODUCTION: Simulation in healthcare has been a widely adopted modality to gain practical experience prior to working directly with patients. While simulation in academic settings affords many opportunities to enhance learning, it may also present an opportunity to identify cultural stereotypes. The objective of this study was to assess the prevalence of gender stereotypes in pharmacy student simulated counseling sessions. METHODS: Simulated counseling sessions completed across several cohorts of pharmacy students were reviewed. A video database of these counseling sessions was manually reviewed retrospectively to determine if students or trained actors portraying the role of the pharmacist and patient, respectively, assigned providers a gender without prompting. Secondary analysis included time to provider gender assignment and acknowledgement. RESULTS: A total of 73 unique counseling sessions were reviewed. Gender was preferentially assigned in 65 sessions. Assigned provider gender was male for all 65 cases. In most (45 out of 65) cases, gender was assigned by the actors. CONCLUSIONS: Predetermined gender stereotypes exist in simulated counseling sessions. Simulation needs to be continually monitored for promoting cultural stereotypes. Integration of cultural competency into counseling simulation scenarios represents an opportunity to better train healthcare professionals to function within a diverse work environment.

Distribution of age, sex, race, and ethnicity in COVID-19 clinical drug trials in the United States: A review.

BACKGROUND: COVID-19 quickly overwhelmed the world, but disproportionately affects certain communities, particularly minority groups. Despite overrepresentation among COVID-19 cases and death, minority groups were underrepresented in some of the early COVID-19 clinical trials. OBJECTIVE: To assess and compare the demographic characteristics of COVID-19 clinical trial participants to national COVID-19 data. METHODS: PubMed was searched from December 1, 2019 to November 24, 2020, for randomized controlled trials evaluating a pharmacologic treatment for COVID-19 patients from one or more U.S. sites written in the English language following the PRISMA checklist. Descriptive statistics were calculated to characterize patient demographics enrolled in the included clinical trials, as well as for comparison with national COVID-19 data. RESULTS: A total of 4472 records were identified, of which 16 studies were included. The median number of participants was higher in studies of nonhospitalized patients compared to those of hospitalized patients (n = 452 [range 20-1062] vs n = 243 [152-2795]). Ten (63%) studies reported mean or median ages of 50 years or older among all study arms. Males comprised more than half of the study cohort in ten (63%) studies. Race and ethnicity were reported separately in four (25%) studies but were combined when reported in five (31%) studies, while six (38%) reported only race or ethnicity. Proportional representation based on age, sex, race, and ethnicity was evident in some trials, but not in others, when compared to national data. CONCLUSION: Overall, participants often did not reflect the actual population with COVID-19 and demographic characteristics were inconsistently reported.

Bitter bottle gourd poisoning: A case report and review of literature.

Bottle gourd juice is considered a panacea in traditional Indian medicine and used in various chronic diseases. Increased levels of Cucurbitacin can turn it bitter causing toxic effects in gastrointestinal system. We report the case of an elderly female who presented with shock in few hours after consumption of bitter bottle gourd juice. After proper evaluation we considered the possibility of bottle gourd poisoning as a probable diagnosis due to the Naranjo adverse drug reactions probability scale. Since there is no specific antidote available, management is mostly supportive with intravenous fluids, control of bleeding and management of shock.

Cellular cross talk between epicardial fat and cardiovascular risk.

A variety of fat compartments have several local and systemic effect and play a crucial role in the maintenance of health and development of disease. For the past few years, special attention has been paid to epicardial fat. It is the visceral fat compartment of the heart and has several local and systemic effects. It can perform a role in the development of cardiometabolic risk. The epicardial adipose tissue (EAT) is a unique and multifunctional fat compartment of the heart. It is located between the myocardium and the visceral pericardium. During normal physiological conditions, the EAT has metabolic, thermogenic, and mechanical (cardioprotective) characteristics. The EAT can produce several adipocytokines and chemokines depending on microenvironments. It can influence through paracrine and vasocrine mechanism and participate in the development and progression of cardiovascular (CVS) diseases. In addition, metabolic disease leads to changes in both thickness and volume of the EAT, and it can modify the structure and the function of heart. It has been associated with various CVS diseases such as, cardiomyopathy, atrial fibrillation, and coronary artery disease. Therefore, EAT is a potential therapeutic target for CVS risk.

Quality aspects in the development of pelletized dosage forms.

The aim of this work was to identify and collate the major common challenges that arise during pellet development. These challenges focus on aspects right from raw material properties until the final drying process of the pelletization. The challenges associated with the particle size of drug and excipients, physicochemical properties, drug excipient interaction and the effect of type/grade and amount of raw material on the pellet properties are covered in this review. Technological and process related challenges within the commonly used pelletization techniques such as extrusion-spheronization, hot-melt extrusion and layering techniques are also emphasized. The paper likewise gives an insight to the possible ways of addressing the quality of pellets during development.

Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection.

Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary 'choice' of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.

Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Non-Alcoholic Steatohepatitis: A Clinical Review Article.

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the lethal causes of chronic liver disease globally. NAFLD can ultimately progress to non-alcoholic steatohepatitis (NASH) given persistent cellular insult. The crux of the problem lies in fat accumulation in the liver, such as increased fatty acid substrates owing to consumption of a high-fat diet, altered gut physiology, and excess adipose tissue. Being the hepatic manifestation of metabolic syndrome, insulin resistance is also among one of the many stimuli. Therefore, drugs, such as glucagon-like peptide-1 receptor agonist (GLP-1 RA) can play a significant role in reducing inflammation, in addition to weight loss and dietary habits. In this review article, we have reviewed the role of exenatide, liraglutide, and semaglutide in the management of NASH. Two of the agents, exenatide and semaglutide, have a predominant role in reducing alanine aminotransferase (ALT) levels, therefore reducing inflammation and promoting weight loss. However, these agents have a lesser impact on the degree of fibrosis. Liraglutide, on the other hand, has been shown to significantly decrease the degree of fibrosis and has been found helpful in reversing mild degrees of steatosis. Therefore, these agents warrant attention to the new perspective that has been presented so that future guidelines may incorporate and streamline individualized therapy.